In recent years, microRNAs (miRNAs, miRs) have emerged as an important novel class of regulatory RNA, which have a profound impact on a wide array of biological processes.
These small (typically 18-24 nucleotides in length) non-coding RNA molecules can modulate protein expression patterns by promoting RNA degradation, inhibiting mRNA translation, and also affecting gene transcription. miRs play pivotal roles in diverse processes such as development and differentiation, control of cell proliferation, stress response and metabolism. The expression of many miRs was found to be altered in numerous types of human cancer, and in some cases strong evidence has been put forward in support of the conjecture that such alterations may play a causative role in tumor progression. There are currently about 900 known human miRs.
Malignant melanoma (MM) is one of the fastest growing malignancies in the United States (Benjamin et al., 2007, Mol Carcinog 46, 671-678), and its associated mortality that continues to rise throughout the world. In addition to well defined genetic lesions, melanomas are characterized by frequent chromosomal aberrations associated with tumor progression (Jonsson et al., 2007, Cell 120, 635-647). In particular, melanomas display a characteristic pattern of genomic alterations involving miRNA genes.
Melanoma patients with brain metastases have short survival and are excluded from most clinical trials. With a median survival of less than 6 months, the development of brain metastases (B-Met) portends a dismal prognosis for melanoma patients (Raizer et al. 2008, Neuro-oncology 10(2):199-207). Clinical trials open to melanoma patients with B-Met are limited, as their poor prognosis precludes entry into most trials of novel agents. In terms of absolute risk, melanoma has a high predilection to metastasize to the brain (Maher et al., 2009, Cancer research 69(15):6015-6020). Compared to other solid malignancies, a higher proportion of melanoma brain metastases represent the only site of metastatic involvement, suggesting a specific CNS-tropism (Thompson J F, Morton D, & Kroon B (2004) Textbook of Melanoma (Martin Dunitz, London) p. 465). This high rate of CNS involvement may be due to a “homing” effect given that melanocytes and neuronal subpopulations such as glial cells share a common neural crest progenitor (Herlyn et al., 2000, Melanoma Res 10(4):303-312). The molecular mechanism responsible for this predilection is unknown, thus one is unable to accurately predict which primary melanoma patients will ultimately develop B-Met. There remains a need for the identification of prognostic variables present early in the melanoma course that can identify patients at highest risk for B-Met who may benefit from increased surveillance and/or prophylactic interventions that target the CNS.